Reviews

Transitions between frailty, prefrailty, and nonfrail states occur.[42] If risk factors for the development of frailty can be identified, interventions to preserve or enhance functional capacity can be instituted concurrently with cancer therapy. The at-risk or prefrail patient is the ideal candidate for preventive interventions to maintain or improve physical function during or after cancer therapy.

Evidence suggests that exercise can minimize several physiologic changes associated with aging.[43] In one study, physically active adults were more likely to survive to age 80 years or more and had half the risk of dying with a disability.[44] Another study showed that even in individuals in home-care programs, active patients were less likely to die than those with no or low-intensity physical activity.[45] This relationship was noted even for patients over age 80.

Resistance training in particular is effective in improving strength and increasing muscle mass in older adults.[46] In a systematic review of 62 randomized clinical trials, Latham identified improvements in muscle strength and gait speed.[48] However, improvement in aerobic capacity and balance was inconsistent. Exercise training appears to be effective in elderly populations considered to be frail, such as those in nursing homes.[43,49] For the very old or frail, scheduled daily activity such as walking or housekeeping can help postpone frailty and prolong independence.[20]

Progression to frailty may also be delayed by managing the chronic conditions and geriatric syndromes identified by CGA. In a pilot evaluation of early breast cancer patients over the age of 70, CGA assessment resulted in 17 interventions per patient and was felt to influence oncologic treatment in 4 of 11 patients.[50] Arnoldi et al evaluated a CGA model in 153 patients over age 70 to help identify those eligible for oncologic treatment or supportive care.[51] The CGA identified 30 borderline and 14 frail individuals. Although therapy choices were not dictated by CGA results, a higher percentage of nonfrail subjects received therapy, and frail subjects were significantly more likely to die in 6 months than nonfrail patients.

In a randomized trial, McCorkle et al evaluated a CGA assessment vs usual postsurgical care in cancer patients undergoing surgery.[52] A home-care intervention was planned based on the comprehensive assessment. Postsurgical cancer patients receiving the specialized CGA-based home-care intervention had improved survival compared to the usual care group. The data available about elderly cancer patients suggest that it is important to identify and consider frailty before finalizing diagnosis and therapy plans.

Treatment of Breast Cancer in the Frail Elderly

Diagnosis and Treatment of the Primary Lesion

The benefits of mammographic screening are questionable in the frail elderly, and such imaging should be avoided for women with an estimated survival of less than 5 years. Annual breast examination should suffice for finding breast cancers serious enough to have an impact on the frail elderly woman's survival and quality of life. Nevertheless, mammography is still likely to be performed in many of these patients and will occasionally detect early nonpalpable breast cancers.

If a suspicious lesion is detected mammographically, the physician is then compelled to evaluate the abnormality, and a biopsy is needed. In general, core biopsy is preferred over fine-needle aspiration since core biopsy is superior in establishing whether the breast lesion represents in situ or invasive carcinoma and can also be used for assessment of estrogen and progesterone receptors. For some frail patients, excision of the breast lesion—especially if it is negative for both estrogen and progesterone receptors—may be the best approach. In most frail patients treated with lumpectomy and whose tumors have clear margins, radiation therapy is not likely to be of any survival benefit and can be omitted. For frail women with hormone receptor–positive lesions, primary endocrine therapy with either tamoxifen or an aromatase inhibitor (AI) should be considered.

A wealth of data exist on the use of tamoxifen as primary therapy in older women with breast cancer, including several randomized trials comparing tamoxifen alone to mastectomy or lumpectomy. Such trials have generally shown no significant difference in survival for tamoxifen-treated patients compared to those receiving surgical intervention. About 75% of women treated with tamoxifen alone have a complete or partial response.

In one trial of 100 frail elderly women with breast cancer, 40% of patients had a complete response (median duration: 47 months) and 22% a partial response (median duration: 26 months). Time to disease progression was about 15 months for the remaining patients.[53] After a median follow-up of about 5 years, only 11% of patients required surgery for local progression. Other trials using tamoxifen alone show similar results. For women with an estimated survival of 5 years, surgery is superior for local control of the primary lesion, but for the frail patient, endocrine therapy alone is likely to provide local control for the duration of the patient's life.

Aromatase inhibitors have been shown to be superior to tamoxifen in randomized trials in the adjuvant, neoadjuvant, and metastatic setting.[54-57] AIs are not associated with an increased risk of endometrial cancer or thromboembolism. Frail elders without hysterectomy are unlikely to have the annual pelvic examinations needed for monitoring tamoxifen therapy, and the lower physical activity levels in frail elders may increase their risk of tamoxifen-related thromboembolism. AIs are associated with a modestly increased risk of fractures compared to tamoxifen, but this risk can be overcome with the use of oral bisphosphonates. For frail patients who progress on initial endocrine therapy, other hormonal agents can be used for disease control. For the frail elder who is not amenable to surgery and who presents with hormone receptor–negative breast cancer, chemotherapy or local radiation therapy might be considered for those with symptoms or rapid tumor growth.

Systemic Adjuvant Therapy

Healthy elders with hormone receptor–positive cancer derive major benefits from tamoxifen therapy, with annual risk reductions in relapse, breast cancer mortality, and new contralateral breast cancer of 30% to 50%.[58,59] The recent meta-analysis conducted by the Early Breast Cancer Trialists' Collaborative Group shows that the majority of breast cancer relapses in hormone receptor–positive patients occurs after 5 years, irrespective of tamoxifen use.

Frail elders with hormone receptor–positive breast cancers are only likely to benefit from adjuvant endocrine therapy with either tamoxifen or AIs if they have an extremely high risk of relapse within a 5-year period. Estimates of the benefits of treatment can be made using the Web-based program Adjuvant! Online (www.adjuvantonline.com). This program factors in the US census–derived mortality data by age, and one can add an estimate of comorbidity to the program to factor in the effect of coexisting illness on treatment benefit. An example of how this can help in treatment selection is shown in Table 5. This example shows that endocrine treatment is likely to be of minimal to no value in improving survival in most frail elders, whose survival would likely be even worse without treatment than that of the patient with poor health used in this example. Moreover, the effectiveness of more intensive chemotherapy (for example, the dose-dense therapy described in this table) when added to endocrine therapy is likely overestimated in this program.

Frail elders with hormone receptor–negative breast cancer and with an expected survival of less than 5 years are not candidates for current adjuvant chemotherapy regimens, even if they have extensive nodal involvement.